It is clear that the progress of diabetes research during the coming decade will depend heavily upon the ability to ufilize the mouse as an experimental model to invesfigate both basic and clinically relevant quesfions in diabetes research. The Transgenic and Knock-out Mouse Core (TKMC, Core A) provides invesfigators at UCLA, UCSD, the Salk Institute, and Cedars-Sinai with a wide array of genefic manipulafions in the mouse including transgenic genes, homologous recombinafion in embryonic stem cells (ES cells), creation of chimeric mice from ES cells, and the most cutting-edge approaches to performing reverse genefics in the mouse. Transgenic, knock-out and knock-in mouse models are created that utilize the most advanced approaches including condifional Tet-inducible and tamoxifen-inducible transgenes, fissue-specific and condifional knock-outs using Cre-LoxP and Flp recombinases and recombinafion-mediated cassette exchange (RMCE), BAC transgenics, BAC-Trap, RiboTag, and other specialized technologies. This Core is an outstanding example of how extraordinarily specialized techniques, highly trained dedicated personnel, specially constructed facilities, and expensive equipment can be accessed by researchers who could not reasonably expect to develop them on an individual basis. Key objectives are: 1. To create innovative and important mouse models for studies of diabetes and its complicafions 2. To eliminate barriers to the most cutfing-edge mouse genefic approaches for the DERC membership 3. To provide outstanding, reliable, and high quality mouse embryology and genefic services 4. To advance the technology of genefic manipulafion of the mouse genome The availability of this Transgenic and Knock-out Mouse Core in coordinafion with the Metabolic and Molecular Physiology Core, the Genomics and Epigenefics Core, and the Novel Target idenfificafion and Assay Development Core, will enable our members to conduct versafile, cutting-edge, reverse genefic research in the mouse with a battery of multidisciplinary, state-of-the-art techniques.